Daily Ards Research Analysis

BACKGROUND: The objective of this study is to delineate the differential gene expression patterns of neutrophils in bronchoalveolar lavage fluid (BALF) from patients with sepsis and those experiencing progression to sepsis-induced acute respiratory distress syndrome (SI-ARDS). Additionally, we aim to comprehensively profile the transcriptomic landscape of neutrophils in BALF from patients with sepsis and SI-ARDS, particularly focusing on cases caused by specific bacterial pathogens. METHODS: Patients with confirmed sepsis (n = 14) or SI-ARDS (n = 11) were recruited. Besides, a control group consisting of patients with unrelated diseases (n = 7) who required bronchoscopy was also included (cohort 1). We collected the neutrophils in BALF from participants in cohort 1. To validate the identified differentially expressed genes (DEGs) and evaluate neutrophil apoptosis, an additional cohort (cohort 2) was recruited, consisting of 5 healthy controls, 10 patients with sepsis, and 10 patients with SI-ARDS. Peripheral blood neutrophils were collected from participants in cohort 2 for further analysis. DEGs between SI-ARDS patients and controls, sepsis patients and controls, as well as SI-ARDS patients and sepsis patients were identified. And, publicly available datasets were downloaded to compare with local results. Additionally, the DEGs were also identified between patients infected with drug-resistant Klebsiella pneumoniae and those infected with other bacterial pathogens. Furthermore, a third cohort (cohort 3) consisting of 57 sepsis patients and 46 SI-ARDS patients was recruited for investigating the prognostic significance of neutrophils in SI-ARDS. RESULTS: In cohort 1, 8/14 of the septic patients and 6/11 of the SI-ARDS patients were affected by drug-resistant Klebsiella pneumonia. There were 9921 DEGs between sepsis patients and controls, 10,252 DEGs between SI-ARDS patients and controls, and 24 DEGs between SI-ARDS and sepsis patients in neutrophils from BALF. Notably, fatty acid-binding pro-tein 4 (FABP4) exhibited significant downregulation in SI-ARDS patients. In cohort 2, peripheral blood analysis confirmed consistent trends, demonstrating that FABP4 expression was decreased, which contributed to the attenuation of neutrophil apoptosis. And FABP4 inhibitor-induced apoptosis resistance was reversed by a phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) inhibitor. Furthermore, survival analysis revealed that SI-ARDS patients with low levels of neutrophil FABP4 expression exhibited poor survival. Additionally, 520 overlapping DEGs were identified between the sepsis and control group comparisons and the SI-ARDS and sepsis group comparisons. Among these overlapping DEGs, 85% were downregulated, predominantly targeting immune-related pathways, whereas a smaller subset was upregulated, mainly associated with metabolism. DEGs in neutrophils in BALF of SI-ARDS and controls notably overlapped with those in neutrophils in peripheral blood. Importantly, DEGs in sepsis/SI-ARDS caused by drug-resistant Klebsiella pneumoniae differed from DEGs in sepsis/SI-ARDS caused by other bacteria. Additionally, FABP4 expression consistently decreased, attenuating neutrophil apoptosis. CONCLUSIONS: The downregulation of FABP4 in neutrophils was found to inhibit apoptosis through the activation of the PI3K/AKT signaling pathway. Importantly, the expression level of FABP4 in neutrophil emerged as a prognostic indicator for sepsis and SI-ARDS patients, suggesting its potential utility in clinical decision-making to address the challenges posed by this condition.

BACKGROUND: Mechanical ventilation requires frequent reassessment from providers to ensure delivery of lung protective ventilation. However, in resource-limited settings, the time and attention lung protective ventilation requires are not always feasible. This study aimed to compare a physiologic closed-loop control (PCLC) ventilator capable of self-adjusting based on patient parameters against standard of care (SOC) ventilatory management in a porcine model. METHODS: The study compared SOC (n = 15) with PCLC (n = 15) for three porcine injury models: hemorrhage, lung injury, and hemorrhage with lung injury. Hemorrhage animals were progressively bled to three mean arterial pressures (60, 50, and then 40 mm Hg) and monitored for 60 minutes after each bleed. Lung injury used saline surfactant washout to a targeted PO 2 /fraction of inspired oxygen (FiO 2 ) ratio of <250 mm Hg. Hemorrhage with lung injury combined surfactant washout followed by hemorrhage. Study end points were defined by the percent of time spent within target values: Acute Respiratory Distress Syndrome Network concordance, oxygenation (>96% with FiO 2 0.21% or oxygen saturation [SpO 2 ] <92% on FiO 2 1.00%), tidal volume (4 ≤ V T /kg ≤ 10 mL/kg), and plateau pressure (≤30 cm H 2 O). RESULTS: Standard of care animals spent a lower percentage of time within targeted SpO 2 range compared with PCLC (49% ± 25% vs. 68% ± 24% of time, p = 0.04) across all injury models, while all other parameters were comparable. In the hemorrhage group, the percentage of time within targeted SpO 2 was also lower in SOC compared with PCLC ( p = 0.01), while the remaining parameters, and all parameters within lung injury alone and hemorrhage with lung injury were otherwise equivalent ( p > 0.05). CONCLUSION: Physiologic closed-loop control performed equally to or better than SOC during both hemorrhage and lung injury. Physiologic closed-loop control has the potential to provide intensive care unit-level ventilator management in resource-limited circumstances, both in civilian and military operations. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Severe COVID-19 is often complicated by hypoxemic respiratory failure and acute respiratory distress syndrome (ARDS). Mechanisms governing lung injury and repair in ARDS remain poorly understood. We hypothesized that plasma proteomics may uncover protein biomarkers correlated with COVID-19 ARDS severity. We analyzed the plasma proteome from 32 patients with ARDS and COVID-19 using an aptamer-based platform of 7289 proteins, and correlated protein measurements with sequential organ failure assessment (SOFA) scores at days 1 and 7 of ICU admission. We identified 184 differentially abundant proteins correlated with SOFA at day 1 and 46 proteins at day 7. In a longitudinal analysis, we correlated dynamic changes in protein abundance and SOFA between days 1 and 7 and identified 40 significant proteins. Pathway analysis of significant proteins identified increased ephrin signaling and acute phase response signaling correlated with increased SOFA scores between days 1 and 7, while pathways related to pulmonary fibrosis signaling and wound healing had a negative correlation. These findings suggest that persistent inflammation may drive disease severity, while repair processes correlate with improvements in organ dysfunction. This approach is generalizable to future ARDS cohorts for identification of biomarkers and disease mechanisms as we strive towards targeted therapies in ARDS.